The Marfan syndrome, a prototype of inherited disease of connective tissue, clearly involves aberrations in the extracellular matrix of the connective tissue, yet the underlying molecular defect(s) is unknown. In this grant application, we are proposing a concentrated, multidisciplinary effort to study the biochemistry of connective tissue in the Marfan syndrome. The experiments are designed to test the hypothesis that a structural or metabolic alteration in collagen and/or elastin is the underlying defect. Two different approaches will be utilized: First, tissues, such as aorta and skin, will be obtained from the patients with the Marfan syndrome. For comparison, tissues from patients with dissecting aneurysm but without stigmata of the Marfan syndrome, as well as from matched controls will be obtained. Secondly, skin fibroblast cultures will be established from affected and unaffected members of the families with the syndrome. In addition, we plan to establish smooth muscle cell and endothelial cell cultures from aortae. The studies on collagen include identification of the genetic types, assay of cross-links, and isolation for detailed chemical analyses. The studies on elastin include cross-link analyses and determination of chemical composition. Also, we will assay lysyl oxidase activity in tissues and cell cultures employing radioactive collagen and elastin as substrates. Finally, the biochemical findings will be correlated to the structural organization of tissues by light and electron microscopy, as well as to the mechanical properties of the tissues.